This proposal will investigate the synthesis of the highly strained diterpene ingenol. Derivatives of ingenol posses a wide array of biological activity, including anti-tumor, tumor-promoting, and anti-HIV activity. Given the interesting activity of these compounds, there is a great need for synthetic derivatives to establish structure-activity relationships, which may ultimately lead to the development of therapeutic compounds. Although there has been considerable synthetic effort towards ingenol, a total synthesis has not been completed. The critical synthetic feature of the ingenol is the strained "inside, outside" or trans intrabridgehead stereochemistry of the BC ring juncture. The ring closing metathesis (RCM) reaction has emerged as a powerful method for the construction of a variety of cyclic olefins and may be applied to the construction of this strained system. Experiments will be conducted to determine if the ring closing metathesis methodology can be applied first to models of the ingenol ring system, and then towards a total synthesis of ingenol.